Taiwo Odunayo Anthonia, Dosumu Oluwatosin Adebisi, James Adewale Segun, Ugwor Emmanuel Ifeanyichukwu, Ojo Oluwafemi Adeleke, Dedeke Gabriel Adewunmi, Ademuyiwa Oladipo
Department of Biochemistry, College of Natural and Applied Sciences, Chrisland University, Ajebo Abeokuta, Ogun-state, Nigeria.
Department of Biochemistry, College of Biosciences, Federal University of Agriculture Abeokuta, Nigeria.
Toxicol Rep. 2023 Jun 3;10:690-705. doi: 10.1016/j.toxrep.2023.06.001. eCollection 2023.
Cannabis and cannabinoids affect almost every system of the body and exert systemic effects such as alterations in memory and cognitive functions, neurotransmission impediment, as well as obstruction of endocrine and reproductive system functions. Reproduction is a complicated phenomenon that integrates biological, psychological and behavioural aspects, hence susceptible to intracellular and extracellular modulations by numerous chemicals and toxicants like cannabis.
The effects of early-life exposure to cannabis on reproductive function biomarkers and genes were investigated in male and female Wistar rats in this study.
An initial computational analysis (molecular docking and induced fit docking) of some cannabinoids with reproductive enzymes; androgen and follicle stimulating hormone receptors was conducted. Overall, cannabichromene (CBC) had the best IFD scores and binding free energies for the two proteins studied and it interacted with notable amino acids within their active sites. Subsequently, forty (40) Wistar rats, 20 male and 20 female (24-28 days old, weighing 20-28 ± 2 g) were divided into two groups each and orally administered CBC for 21 days. Penile tissues, testes and ovaries, were collected for biochemical analysis (hormonal assays, enzyme activities, and metabolite concentrations), gene expressions, and histological evaluations.
Activities of arginase and phosphodiesterase-5 in the penile tissue were significantly increased, while nitric oxide and calcium levels were significantly (p < 0.05) decreased in the CBC-exposed groups relative to the control group. Semen analysis showed significantly more abnormalities and decreased concentration of spermatozoa in the CBC-exposed group compared to the control. Activities of 17β-hydroxysteroid dehydrogenase and cholesterol level were decreased in both testes and ovaries of CBC-exposed groups. Furthermore, levels of testosterone, progesterone, luteinizing, and follicle-stimulating hormones were reduced in the serum of CBC rats. Moreover, relative expressions of androgen receptor and follicle-stimulating hormone receptor genes were significantly downregulated in the CBC-exposed groups. Histological evaluations revealed lesions, tubular necrosis, and cellular congestions in both the testes and ovaries.
This study suggests that pre-puberty exposure to cannabis modulates reproductive functions via cannabichromene inhibition of steroidogenesis, stimulation of erectile dysfunction (modulation of intermediates and enzymes of the endothelial nitric oxide synthase (eNOS) pathway in the penile tissue), and downregulation of the expressions of genes associated with reproduction.
大麻和大麻素几乎影响身体的每个系统，并产生全身效应，如记忆和认知功能改变、神经传递障碍以及内分泌和生殖系统功能受阻。生殖是一个复杂的现象，整合了生物学、心理学和行为学方面，因此易受大麻等多种化学物质和毒物的细胞内和细胞外调节影响。
本研究在雄性和雌性Wistar大鼠中调查了生命早期接触大麻对生殖功能生物标志物和基因的影响。
对一些大麻素与生殖酶、雄激素和促卵泡激素受体进行了初步的计算分析（分子对接和诱导契合对接）。总体而言，大麻色烯（CBC）在所研究的两种蛋白质中具有最佳的诱导契合对接（IFD）分数和结合自由能，并且它与它们活性位点内的显著氨基酸相互作用。随后，将40只Wistar大鼠（20只雄性和20只雌性，24 - 28日龄，体重20 - 28 ± 2 g）分成两组，每组口服给予CBC 21天。收集阴茎组织、睾丸和卵巢用于生化分析（激素测定、酶活性和代谢物浓度）、基因表达和组织学评估。
与对照组相比，CBC暴露组阴茎组织中的精氨酸酶和磷酸二酯酶 - 5活性显著增加，而一氧化氮和钙水平显著（p < 0.05）降低。精液分析显示，与对照组相比，CBC暴露组的异常情况明显更多，精子浓度降低。CBC暴露组的睾丸和卵巢中17β - 羟基类固醇脱氢酶活性和胆固醇水平均降低。此外，CBC大鼠血清中的睾酮、孕酮、黄体生成素和促卵泡激素水平降低。此外，CBC暴露组中雄激素受体和促卵泡激素受体基因的相对表达显著下调。组织学评估显示睾丸和卵巢均有病变、肾小管坏死和细胞充血。
本研究表明，青春期前接触大麻通过大麻色烯抑制类固醇生成、刺激勃起功能障碍（调节阴茎组织中内皮型一氧化氮合酶（eNOS）途径的中间体和酶）以及下调与生殖相关基因的表达来调节生殖功能。
